Abstract
Pigment epithelium-derived factor (PEDF) is a glycoprotein with complex neuroprotective,
anti-angiogenic, and anti-inflammatory properties, all of which could potentially
be exploited as a therapeutic option for vascular complications in diabetes. We have
previously shown that PEDF-derived synthetic peptide, P5-3 (FIFVLRD) has a comparable
ability with full PEDF protein to inhibit rat corneal neovascularization induced by
chemical cauterization. However, the effects of PEDF peptide on experimental diabetic
nephropathy remain unknown. To address the issue, we modified P5-3 to stabilize and
administered the modified peptide (d-Lys-d-Lys-d-Lys-Gln-d-Pro-P5-3-Cys-amide, 0.2 nmol/day) or vehicle to streptozotocin-induced diabetic rats
(STZ-rats) intraperitoneally by an osmotic mini pump for 2 weeks. We further examined
the effects of modified peptide on human proximal tubular cells. Renal PEDF expression
was decreased in STZ-rats. Although the peptide administration did not affect blood
glucose or blood pressure, it decreased urinary excretion levels of 8-hydroxy-2′-deoxyguanosine,
an oxidative stress marker, and reduced plasminogen activator inhibitor-1 (PAI-1)
gene expression, and suppressed glomerular expansion in the diabetic kidneys. High
glucose or advanced glycation end products stimulated oxidative stress generation
and PAI-1 gene expression in tubular cells, all of which were significantly suppressed
by 10 nM modified P5-3 peptide. Our present study suggests that PEDF-derived synthetic
modified peptide could protect against experimental diabetic nephropathy and inhibit
tubular cell damage under diabetes-like conditions through its anti-oxidative properties.
Supplementation of modified P5-3 peptide may be a novel therapeutic strategy for diabetic
nephropathy.
Key words
AGEs - oxidative stress - PEDF - diabetic nephropathy - RAGE
